The insulin-like growth factors (IGFs), IGF-I and IGF-II, are mitogenic peptide growth factors involved in a broad range of cellular processes including hyperplasia, DNA synthesis, differentiation, cell cycle progression and inhibition of apoptosis (Keiss et al., 1994, Hormone Research 41 66; Wood & Yee, 2000, J. Mammary Gland Biology and Neoplasia 5 1; Jones & Clemmons, 1995, Endocrine Rev. 16 3). These effects are mediated through binding to their tyrosine-kinase linked cell surface receptor, the type 1 IGF receptor (IGF-IR). The IGFs are also tightly regulated by a family of specific binding proteins, termed IGFBPs, whose primary role is to bind free IGFs and thereby moderate their half-life, specificity and activity (Clemmons, 1998, Mol. Cell. Endocrinol. 140 19).
Recently, vitronectin (VN) has been shown to bind directly to IGF-II (Upton et al., 1999. Endocrinology 140 2928-31) while IGF-I can bind to VN in the presence of certain IGFBPs (International Publication WO 02/24219; Kricker et al., 2003, Endocrinol. 144 2807-15). The finding that VN, an ECM organization and adhesion molecule, binds IGF-II with an affinity that is similar to that of IGF-II for IGF-IR (Upton et al., 1999, supra), its biologically relevant receptor, reveals a specific physical link between IGF action and VN in the ECM. In addition, IGF-II bound to VN, and IGF-I bound to VN via IGFBPs, can stimulate synergistic functional responses in a diverse range of cells including human keratinocytes in vitro (International Publication WO 02/24219; Noble et al., 2003, supra; Kricker et al., 2003, supra).
Wounds, burns and ulcers are debilitating and painful skin conditions that require intensive and costly treatments which, in many cases, are only partly successful. For example, more than 520,000 Australians are currently diagnosed with diabetes, and of these, more than 5% will experience foot ulcers. These wounds significantly compromise the quality of life of the patient, often lead to prolonged hospitalisation, and may ultimately result in amputation. In fact, the vast majority of lower limb amputations performed are attributed to a non-healing ulcer.
An increasingly preferred approach to healing wounds, burns and ulcers is to replace dead or damaged skin with autologous or allogeneic keratinocytes grown in vitro. Typically, keratinocytes are grown in defined media in the presence of exogenous factors such as serum or bovine pituitary extracts, usually with feeder cells that optimize keratinocyte growth.